Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• metalloenzyme inhibitor compounds and their use as fungicides.
• the disclosure of this application is expressly incorporated by reference herein.
• This patent application describes various routes to generate metalloenzyme inhibiting fungicides. It may be advantageous to provide more direct and efficient methods for the preparation of metalloenzyme inhibiting fungicides and related compounds, e.g., by the use of reagents and/or chemical intermediates which provide improved time and cost efficiency.
• halogen refers to one or more halogen atoms, defined as F, CI, Br, and I.
• organometallic refers to an organic compound containing a metal, especially a compound in which a metal atom is bonded directly to a carbon atom.
• Room temperature is defined herein as about 20 °C to about 25 °C.
• references to the compounds of Formula I- II are read as also including optical isomers and salts. Specifically, when compounds of Formula I-II contain a chiral carbon, it is understood that such compounds include optical isomers and racemates thereof.
• Exemplary salts may include: hydrochloride, hydrobromide, hydroiodide, and the like.
• Method A Bubbling air through the reaction mixture.
• reaction mixture was stirred at 180 °C for 4 h. After this time the reaction mixture was cooled to 160 °C and maintained at this temperature with stirring for an additional 12 h. After this time the mixture was analyzed by HPLC, which indicated complete consumption of starting material.
• the reaction mixture was cooled to room temperature and the air purge was turned off. The mixture was diluted with EtOAc (100 mL) and filtered through a Celite ® pad. The EtOAc layer was washed with brine (20 mL) and water (20 mL).
• Method B Bubbling nitrogen through the reaction mixture.
• the reaction mixture was heated at 180 °C for 5 h, after which it was cooled down to 20 °C and the reaction mixture was diluted with MTBE (700 mL).
• Activated carbon 90 g, Darco KB; about 100 mesh
• the mixture was filtered through a pad of Celite ® , and the filter cake was rinsed with MTBE (2x800 mL).
• the combined filtrate and rinses were washed with brine (3x1000 mL) and the first aqueous wash was extracted with MTBE (400 mL).
• the combined organic layers were extracted with 1 N NaOH (2.4 L) and the aqueous layer was re-extracted with DCM (2x1.2 L).
• EtOAc (2.4 L) was added to the aqueous layer and the pH was adjusted to 3 with HC1 (37 wt%, 200 mL). The organic layer was separated and washed with saturated NaHC0 3 (2x1200 mL) and brine (3x1000 mL), dried over anhydrous Na 2 S0 4 , and filtered. The filtrates were concentrated to provide an off-white foam (47 g). The material was suspended in 50% EtOAc/hexanes (1440 mL) for 15 min at 55 °C and filtered. The solid was further slurried in 500 mL of EtOAc/hexanes (1 : 1) and filtered. The filter cake was further dried under vacuum to afford an off-white solid (25 g).
• Method C Bubbling nitrogen through the reaction mixture with alternative isolation.
• 4-((6-(2-(2,4-Difluorophenyl)- 1 , 1 -difluoro-2-hydroxy-3 -( 1H- 1 ,2,4-triazol- 1 - yl)propyl)pyridin-3-yl)oxy)benzonitrile (II) (5 g, 10.65 mmol) and elemental sulfur (3.42 g, 107 mmol) were suspended in NMP (40 mL) in a 3-neck 250-mL round bottom flask. The flask was fitted with a thermocouple and an air condenser.
• a needle was inserted from a compressed nitrogen inlet line and nitrogen was gently bubbled through the reaction mixture during the course of the reaction.
• the reaction mixture was stirred at 180 °C for 7 h.
• MTBE 100 mL was added to the reaction mixture and it was filtered through a pad of Celite ® .
• To the filtrate was added water (100 mL) and the mixture was filtered again through Celite ® and the phase separated.
• the aqueous layer was extracted with MTBE (50 mL) and the combined organic layers were extracted with 1 M NaOH (100 mL).
• the aqueous layer was washed with DCM (50 mL) then extracted with ethyl acetate (100 mL).
• the ethyl acetate layer was washed with brine (50 mL). To the organic layer was added water (50 mL) and the mixture was acidified to pH 5 using 2 M HC1. The phases were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated to half of its volume. The product was crystallized from the ethyl acetate solution by addition of heptane (50 mL) giving the desired product as a white solid (3.77 g, 69% yield). Spectral data matched those described above.
• Suitable solvents for use in this process step may be selected from at least one of dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), sulfolane, and N-methyl-2-pyrrolidone (NMP).
• DMSO dimethylsulfoxide
• DMF N,N-dimethylformamide
• DMAc N,N-dimethylacetamide
• NMP N-methyl-2-pyrrolidone

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Plural Heterocyclic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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• 2017
  • 2017-11-17 CN CN201780071026.7A patent/CN110418786A/zh active Pending
  • 2017-11-17 US US16/462,198 patent/US20190330184A1/en not_active Abandoned
  • 2017-11-17 BR BR112019009767A patent/BR112019009767A2/pt not_active Application Discontinuation
  • 2017-11-17 WO PCT/US2017/062150 patent/WO2018094139A1/en unknown
  • 2017-11-17 EP EP17870878.0A patent/EP3541795A4/de not_active Withdrawn

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